Diphenylheteroalkyl derivatives, the preparation thereof and drugs and cosmetics prepared therefrom

ABSTRACT

Abstract of the Disclosure: Diphenylheteroalkyl derivatives of the formula I ##STR1## where A and R 1  -R 6  have the meanings specified in the description, and the preparation thereof are described. 
     The substances are suitable for controlling diseases and as cosmetic agents.

This is a division of application Ser. No. 07/469,063, filed on Jan. 23,1990, now U.S. Pat. No. 5,087,743.

It has been disclosed that stilbene derivatives [cf. DE-A 2,854,354,DE-A 3,534,564 and EP 212,137 (U.S. Pat. No. 4,588,750)] which containthe polyene structure of substances of the vitamin A type fixed inaromatic rings have pharmacological effects on topical and systemictherapy of neoplasms, acne, psoriasis and other dermatologicaldisorders. The effect of these compounds is, however, not alwayssatisfactory [cf. G. L. Peck in: The Retinoids, vol. II, (1984) 391-409,ed. M. B. Sporn et al., Academic Press N.Y., or R. Marks et al., Med. J.Australia 146 (1987) 374-377 or C. E. Orfanos et al., Drugs 34 (1987)459-503].

The object of the invention was therefore to develop compounds with animproved spectrum of action.

We have now found, surprisingly, that diphenylheteroalkyl derivatives ofthe formula I ##STR2## where A is --E--CH₂ -- or ##STR3## where E can belinked to the left or right phenyl nucleus and is oxygen, --S(O)_(n) --or --NR⁷ -- (with n being 0, 1 or 2),

R¹, R² and R³ are, independently of one another, hydrogen or halogen,C₁₋₆ -alkyl or OR⁷, and one of the three radicals can also be nitro,

R⁴ and R⁵ are, independently of one another, hydrogen, OR⁷, C₁₋₆ -alkylor together form a --C(CH₃)₂ --B--C(CH₃)₂ -- ring (with B being --CH₂CH₂ --, --CH₂ CO--, --CH₂ CHOH--, --CH═CH-- or --CH(CH₃)--) or a--O--C(CH₃)(Z)--CH₂ --CH₂ -- ring (with Z=methyl or ethyl, each of whichcan be substituted by OR⁷),

R⁶ is hydrogen, methyl, nitro, cyano, tetrazolyl or --CH₂ OR⁷, --OR⁸ --,--NR⁹ R¹⁰, --CH₂ NR⁹ R¹⁰, --CH(OR¹¹)₂, --SR¹⁰, --S(O)_(n) R¹² (n=1,2),--PO(OR¹³)₂, --NR¹³ OR¹⁹, --SO₃ H or --C(O)R¹⁴, where

R⁷ is hydrogen, C₁₋₆ -alkyl or C₁₋₆ -alkanoyl,

R⁸ is hydrogen, C₁₋₆ -alkyl, C₁₋₆ -alkanoyl, or benzoyl which can besubstituted, or --CH₂ --C(O)R¹⁵ -- (with R¹⁵ being hydrogen, C₁₋₆-alkyl, C₁₋₆ -alkanoyl, hydroxyl or --NR¹⁶ R¹⁷),

R⁹ and R¹⁰ are, independently of one another, hydrogen, C₁₋₄ -alkyl,C₁₋₄ -alkanoyl, or benzyl or benzoyl which can be substituted byhydroxyl or C₁₋₄ -alkoxy,

R¹¹ is C₁₋₆ -alkoxy, it being possible for the two R¹¹ radicals to forma cyclic acetal with the CH group,

R¹² is C₁₋₆ -alkyl,

R¹³ and R¹⁹ are, independently of one another, hydrogen or C₁₋₃ -alkyl.

R¹⁴ is hydrogen or halogen, hydroxyl, C₁₋₆ -alkyl, C₁₋₆ -alkoxy, orphenoxy or benzyloxy which can be substituted by hydroxyl or C₁₋₄-alkoxy, or --NR¹⁶ R¹⁷ with R¹⁶ and R¹⁷ being, independently of oneanother, hydrogen, C₁₋₄ -alkyl, or benzyl which can be substituted byhydroxyl or C₁₋₄ -alkoxy,

as well as the physiologically tolerated salts thereof where appropriatehave an improved spectrum of action.

Preferred compounds of the formula I are those in which A has theabovementioned meaning and X is an ether, thioether or NH bridge.

Preferred halogens for R¹, R² and/or R³ are fluorine and chlorine.

Preferred C₁₋₆ -alkyls for R⁴ and/or R⁵ are branched rather than linear.

Further preferred compounds of the formula I are those in which R⁶ is--CH₂ OR⁷, --OR⁸ --SR¹⁰, --S(O)₂ R¹², SO₃ H, --PO(OR¹³)₂ or --C(O)R¹⁴ ;among these the particularly preferred compounds are those in which R⁷is hydrogen, R⁸ is hydrogen, acetyl, or benzoyl which is preferablysubstituted one or more times by amino, acetamino, dimethylamino,hydroxyl, methoxy, methyl or halogen, in particular fluorine orchlorine, and R¹⁰ is hydrogen, acetyl, or benzoyl which is preferablysubstituted one or more times by amino, acetamino, dimethylamino,methoxy, methyl or halogen, in particular fluorine or chlorine, R¹² ismethyl or ethyl, R¹³ and R¹⁹ are hydrogen or methyl, R¹⁴ is hydrogen,hydroxyl, methyl, methoxy, ethoxy or phenoxy, which can be substitutedone or more times by amino, acetamino, dimethylamino, hydroxyl ormethoxy, or is --NR¹⁶ R¹⁷ with R¹⁶ and/or R¹⁷ preferably being hydrogen,methyl or benzyl, which can be substituted one or more times by acetoxy,hydroxyl or methoxy, or with R¹⁶ being hydrogen and R¹⁷ being OH.

Some of the novel compounds of the formula I contain chiral centers andare generally produced as diastereomer mixtures or racemates. Thediastereomers can be separated, for example, by differences insolubility or by column chromatography, and isolated in pure form. Pureenantiomers can be obtained from the pairs of enantiomers byconventional methods. The present invention relates both to the pureenantiomers and to the mixtures thereof (racemates). Both the purediastereomers or enantiomers and the mixtures thereof can be used astherapeutic or cosmetic agents.

Some of the compounds according to the invention have an acidic hydrogenand can therefore be converted with bases in a conventional manner intoa physiologically tolerated salt which is readily soluble in water.Examples of suitable salts are ammonium and alkali metal salts,especially of sodium, potassium and lithium, or alkaline earth metalsalts, especially of calcium or magnesium, as well as salts withsuitable organic bases such as with lower alkylamines, e.g. methylamine,ethylamine or cyclohexylamine, or with substituted lower alkylamines,especially hydroxyl-substituted alkylamines, such as diethanolamine,triethanolamine or tris(hydroxymethyl)aminomethane and with piperidineor morpholine.

The amines of the formula I according to the invention can be convertedby conventional methods into the acid addition salt of a physiologicallytolerated acid. Examples of suitable physiologically tolerated organicor inorganic acids are: hydrochloric acid, hydrobromic acid, phosphoricacid or sulfuric acid, and of organic acids are maleic acid, fumaricacid, lactic acid, tartaric acid, malic acid, citric acid, salicylicacid, adipic acid or benzoic acid. Others can be found in "Fortschritteder Arnzeimittelforschung" volume 10, 1966, pages 224-225, BirkhauserVerlag, Basle and Stuttgart.

The present invention also relates to a process for the preparation ofthe abovementioned compounds of the formula I, by

a) if A is --O--CH₂ -- or --O--CH(CH₃)--, reacting phenols of theformula II ##STR4## where R¹ -R⁵ have the abovementioned meanings, withbenzyl derivatives of the formula III ##STR5## where R⁶, has theabovementioned meaning, R¹⁸ is hydrogen or methyl, and X is anucleofugic leaving group, or

b) if A is --CH₂ --O-- or --CH(CH₃)--O--, reacting phenols of theformula IV ##STR6## where R⁶ has the abovementioned meaning, with benzylderivatives of the formula V ##STR7## where R¹ -R⁵, R¹⁸ and X have theabovementioned meanings, or

c) if A is --S(O)_(n) --CH₂ -- or --S(O)_(n) --CH(CH₃)--, reactingthiophenols of the formula VI ##STR8## where R¹ -R⁵ have theabovementioned meanings, with benzyl derivatives of the formula III togive thioethers (n=0), it then being possible to oxidize the latter togive the corresponding sulfoxides (n=1) or sulfones (n=2), or

d) if A is --CH₂ --S(O)_(n) -- or --CH(CH₃)--S(O)_(n) --, reactingthiophenols of the formula VII ##STR9## where R⁶ has the abovementionedmeaning, with benzyl derivatives of the formula V to give thioethers(n=0), it then being possible to convert the latter into thecorresponding sulfoxides (n=1) or sulfones (n=2), or

e) if A is --NR⁷ CH₂ -- or --NR⁷ CH(CH₃)--, either

1. reacting anilines of the formula VIII ##STR10## where R¹ -R⁵ and R⁷have the abovementioned meanings, with benzyl derivatives of the formulaIII as under a) or

2. reacting anilines of the formula VIII with carbonyl compounds of theformula IX ##STR11## where R⁶ and R¹⁸ have the abovementioned meanings,in the presence of a reducing agent; or

f) if A is --CH₂ NR⁷ -- or --CH(CH₃)NR⁷ --, either

1. reacting anilines of the formula X ##STR12## where R⁶ and R⁷ have theabovementioned meanings, with benzyl derivatives of the formula V asunder b), or

2. reacting anilines of the formula X with carbonyl compounds of theformula XI ##STR13## where R¹ -R⁵ and R¹⁸ have the abovementionedmeaning, in the presence of a reducing agent

The alkylating reactions a) - d) and e1) and f1) are carried out in aconventional manner, in the presence or absence of a solvent or diluent,with or without addition of an inorganic or organic base and of areaction accelerator, at temperatures from 10° to 120° C. The preferredsolvents or diluents include ketones such as acetone, methyl ethylketone or cyclohexanone, nitriles such as acetonitrile, esters such asethyl acetate, ethers such as diethyl ether, tetrahydrofuran or dioxane,sulfoxides such as dimethyl sulfoxide, amides such as dimethylformamide,dimethylacetamide or N-methylpyrrolidone, as well as sulfolane ormixtures thereof.

Nucleofugic leaving groups are preferably bromine chlorine,methylsulfonyloxy, trifluoromethylsulfonyloxy and tolylsulfonyloxy.

Examples of suitable bases, which can also be used as acid-bindingagents in the reaction, are alkali metal hydroxides such as lithium,sodium or potassium hydroxide; alkali metal carbonates such as sodium orpotassium carbonate or sodium and potassium bicarbonate, pyridine or4-dimethylaminopyridine. However, it is also possible to use otherconventional bases.

Suitable and preferred reaction accelerators are metal halides such assodium iodide or potassium iodide, quaternary ammonium salts such astetrabutylammonium chloride, bromide or iodide, benzyltriethylammoniumchloride or bromide or crown ethers such as 12-crown-4, 15-crown-5,18-crown-6, dibenzo-18-crown-6 or dicyclohexano-18-crown-6.

The reaction is generally carried out at from 20° to 150° C., underatmospheric or superatmospheric pressure, continuously ordiscontinuously.

The oxidation reactions of the thioethers mentioned under c) and d) arecarried out in the presence or absence of a solvent or diluent, and withor without the addition of a catalyst, by reacting 1.0 equivalent of thethioether with 1.0 to 1.1 equivalents of the oxidizing agent at from-30° to 120° C. to give the corresponding sulfoxide.

The corresponding sulfones are prepared by using 2.0 to 3.0 equivalentsof oxidizing agent. The preferred solvents or diluents include loweralkyl carboxylic acids such as formic acid, acetic acid and propionicacid, alcohols such as methanol, ethanol or isopropanol, hydrocarbonssuch as hexane, cyclohexane or heptane, aromatic compounds such asbenzene, toluene or xylene, ethers such as methyl tert-butyl ether,diisopropyl ether or diphenyl ether, ketones such as acetone or methylethyl ketone, halohydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, dichloroethane or chlorobenzene, as well asnitriles such as acetonitrile and propionitrile or amides such asdimethylformamide, dimethylacetamide or pyrrolidine, as well as water;however, mixtures thereof are also suitable.

Suitable oxidizing agents are the following: peroxy compounds such ashydrogen peroxide, tert-butylhydroperoxide, peracetic acid, perbenzoicacid, monoperphthalic acid or halogenated perbenzoic acids such asm-chloroperbenzoic acid. However, it is also possible to use otheroxidizing agents such as potassium permanganate, potassium dichromate,sodium periodate or periodic acid as well as nitric acid and nitrousgases such as nitrogen dioxide (cf. for example "Methoden derOrganischen Chemie" Ed. Eugen Muller, vol. IX, pp. 207 et seq. and 223et seq., Thieme Verlag, Stuttgart 1955, and Reid "Organic Compounds ofBivalent Sulfur", vol. 2, pp. 64 et seq., Chem. Publ. New York, 1960).

Suitable catalysts are mineral acids such as hydrochloric acid orsulfuric acid, as well as alkali metal hydroxides such as sodium orpotassium hydroxide and alkali metal carbonates such as sodium orpotassium carbonate.

In cases where the reaction takes place in a two-phase system, it ispossible to use phase-transfer catalysts, e.g. quaternary ammoniumcompounds such as tetrabutylammonium salts, to accelerate the reaction.

The alkylating reactions e2) and f2) are carried out by conventionalmethods of reductive alkylation, in the presence or absence of a solventor diluent, with or without the addition of a reaction accelerator. Thereaction is generally carried out at from 20° to 150° C., underatmospheric or superatmospheric pressure, continuously ordiscontinuously.

The aniline and carbonyl components are employed in the ratio from 0.5:1to 2:1, preferably in the equimolar ratio.

The preferred solvents include hydrocarbons such as heptane,cyclohexane, toluene or xylene, and ethers such as diethyl ether,tetrahydrofuran or dioxane, halohydrocarbons such as dichloromethane,trichloromethane or chlorobenzene, alcohols such as methanol, ethanol,isopropanol or cyclohexanol, alkylcarboxylic acids such as formic acid,acetic acid or propionic acid, and acetonitrile, water or mixturesthereof.

Suitable reducing agents are formic acid, hydrogen or metal hydridessuch as lithium aluminum hydride, sodium borohydride or sodiumcyanoborohydride.

However, other reducing agents can also be employed [cf. "Methoden derOrganischen Chemie", Ed. Eugen Muller, vol. XI/1, pp. 618 et seq., 648et seq., 669 et seq., Thieme Verlag, Stuttgart 1957, or Watanabe et al.Tetrahedron Lett. (1974) 1879].

Suitable and preferred hydrogenation catalysts in homogeneous orheterogeneous phase are nickel, cobalt and platinum catalysts (cf. Markoet al., J. Organomet. Chem. 81, (1974) 411, and Rylander "CatalyticHydrogenation over Platinum Metals", pp. 291-303, Academic Press, N.Y.1967).

The starting compounds of the formula II are known or can be obtained bythe conventional methods for preparing substituted phenol derivatives("Methoden der Organischen Chemie", ed. Eugen Muller, vol. VI/1c, pp. 4et seq., 313 et seq., 925 et seq., Thieme Verlag, Stuttgart, 1976).

The benzyl derivatives of the formula III in which X is bromine orchlorine are known or can be prepared from the correspondingalkylbenzene derivatives (X=hydrogen) by halogenation in a conventionalmanner ("Methoden der Organischen Chemie", ed. Eugen Muller, vol. V/3,pp. 735 et seq., 809, Thieme Verlag, Stuttgart, 1962 and vol. V/4, pp.219 et seq., Thieme Verlag, Stuttgart, 1960; W. Foerst: "Neuere Methodender praparat. org. Chemie", vol. III, p. 134, Verlag Chemie, Weinheim,1961).

Benzyl derivatives of the formula III in which X is OH are known in somecases or are prepared by reduction of the corresponding carbonylderivatives of the formula IX. The reactive esters of the formula III inwhich X is a nucleofugic leaving group are prepared from the latter byconventional methods (Houben-Weyl-Muller, Methoden der organischenChemie, Georg Thieme Verlag, Stuttgart 1955, vol. IX, pages 388, 663 and671). Examples of esters of this type are methanesulfonates,trifluoromethanesulfonates, 2,2,2-trifluoroethanesulfonates,nonafluorobutanesulfonates, 4-methylbenzenesulfonates,4-bromobenzenesulfonates, 4-nitrobenzenesulfonates or benzenesulfonates.

The starting compounds of the formula IV are known or are obtained byconventional processes for the preparation of substituted phenols,corresponding to the methods indicated above for the preparation ofcompounds of type II.

The benzyl derivatives of the formula V in which X is bromine orchlorine are known. They can be prepared from the correspondingalkylbenzene derivatives (X=hydrogen) by halogenation in a conventionalmanner (see references for the starting materials of the formula III).

Compounds of the formula V in which X is a reactive ester are obtainedin a manner corresponding to that indicated above for the precursors ofthe formula III, by reducing the corresponding carbonyl compounds of theformula XI and subsequently converting into the reactive esters.

The starting compounds of the formula VI are known or can be obtained bythe conventional processes for the preparation of thiophenols (K.-D.Gundermann and K. Humke in "Methoden der Organischen Chemie", vol. E11,pp. 32 et seq., Thieme Verlag, Stuttgart, 1985 and literature citedtherein). It is possible and preferable to prepare them by reducing thecorresponding sulfonic acid derivatives, for example with metalhydrides, or from the corresponding phenols of the formula II, which areconverted into thiocarbamic esters (Newman and Karnes, J. Org. Chem. 31(1966) 3980).

The starting compounds of the formula VII are known or can be preparedby conventional processes, described above for the thiophenols of theformula VI.

The starting compounds of the formula VIII are known or are prepared ina conventional manner, for example by reducing the corresponding nitrocompounds ("Methoden der Organischen Chemie", ed. E. Muller, vol. XI/1,p. 394, Thieme-Verlag, Stuttgart, 1957).

The starting compounds of the formula IX are known or are obtained byconventional methods for preparing acetophenones, for example byFriedel-Crafts acylation (H. O. House: "Modern Synthetic Reactions", 2nded., W. A. Benjamin Inc. Menlo Park, Calif., (1972), pp. 797 et seq.,and literature cited therein) or by oxidizing the correspondingalkylbenzenes (H. O. House, loc. cit., pp. 288 et seq. and literaturecited therein) and for the preparation of benzaldehydes, for example byVilsmeier aromatic formylation (cf. De Meheas, Bull. Soc. Chem. Fr.(1962) 1989-1999 and literature cited therein) or by reducing thecorresponding benzoyl halides (cf. Fuson in: Patai, "The Chemistry ofthe Carbonyl group", vol. 1, pp. 211-232, Interscience Publ., N.Y. 1966or Wheeler in: Patai, "The Chemistry of Acyl Halides", pp. 231-251,Interscience Publ. N.Y. 1972) or benzonitriles (cf. J. March: "AdvancedOrganic Chemistry, 2nd ed., McGraw-Hill Kogakusha Ltd. Tokyo, 1977, pp.835-836 and literature cited therein).

The starting compounds of the formula X are known or are prepared byconventional methods similar to those indicated above for thepreparation of anilines of type VIII.

The starting compounds of the formula XI are known (e.g. DE-A 3,602,473,DE-A 3,434,942, DE-A 3,434,944) or are obtained by the process indicatedabove for the preparation of carbonyl compounds of the structure IV.

The compounds of the formula I according to the invention in which Acontains an NR⁷ group where R⁷ is hydrogen are converted by conventionalmethods of N-alkylation or N-acylation into other compounds of theformula I according to the invention.

The substances prepared by the abovementioned processes a-f cansubsequently be further modified as follows: The benzoic esters of theformula I (R⁶ =carboalkoxy) are, if desired, hydrolyzed to give the freecarboxylic acids. Of course, it is conversely possible to esterify thefree acid in a conventional manner.

The hydrolysis/esterification is expediently carried out in the presenceof a diluent or solvent, for example a dialkyl glycol ether or cyclicether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a loweraliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutylketone, or in a lower aliphatic alcohol such as methanol, ethanol,propanol or isopropanol, or in dimethyl sulfoxide, or in mixtures of thesaid solvents with water.

Preferred solvents are aqueous mixtures of ethanol, methanol anddimethyl sulfoxide, in which case the reaction is carried out at theboiling point of the reaction mixture.

The hydrolysis is preferably carried out in the presence of alkali, suchas alkali metal hydroxides, carbonates or bicarbonates, especially ofsodium or potassium, organic tertiary bases such as pyridine or lowertrialkylamines, such as trimethyl- or triethylamine, mixed with water.The ratio of the base to the ester is stoichiometric, or the base isemployed in slight excess. Sodium or potassium hydroxide is preferablyused.

The esterification is advantageously carried out by first converting thecarboxylic acid into its salt and treating the latter with anappropriate alkyl halide, preferably an alkyl bromide or iodide.Particularly suitable deprotonating agents for preparing the salts insitu are the carbonates, hydroxides and hydrides of the alkali metals.It is expedient to use aprotic polar solvents such as acetone,dimethylformamide, dimethyl sulfoxide and, in particular, methyl ethylketone, in which case the reaction is carried out at the boiling pointof the reaction mixture.

The amides according to the invention can be prepared in a conventionalmanner by first converting the benzoic acids I (R⁶ ═COOH) into moreactive derivatives, e.g. into the carbonyl halides, azides, imidazolidesor anhydrides, the O-acyl-N,N,-dicyclohexylisoureas or p-nitrophenylesters, and treating the latter with amines HNR¹⁶ R¹⁷. In the case ofparticularly reactive amines, especially ammonia, direct aminolysis ofesters (having the radical --C(O)R¹⁴ where R¹⁴ is alkoxy) is preferred.

The hydroxamic acid derivatives of the formula I (R⁶ ═CONR¹³ OR¹⁹)according to the invention were prepared from the corresponding benzoicacids I (R⁶ ═CO₂ H) by reacting their activated carbonyl derivativeswith hydroxylamines of the type NHR¹³ OR¹⁹, preferably in a polaraprotic solvent such as dimethylformamide, with equimolar amounts of anorganic or inorganic base as proton trap, at room temperature to theboiling point of the reaction mixture. The reaction is carried out underatmospheric or superatmospheric pressure. Hydroxylamine is preferablyemployed in the form of its salt with a mineral acid, especially as thehydrochloride, and using a further equivalent of base.

A carboxylic acid or ester or amide thereof of the formula I (R⁶═C(O)R¹⁴) can be reduced in a conventional manner to the correspondingalcohols or amines. The reduction is advantageously carried out with ametal hydride or alkali metal hydride in the presence of a suitablesolvent. Preferred metal hydrides are complex metal hydrides such aslithium aluminum hydride or diisobutylaluminum hydride. The solventsused with lithium aluminum hydride are ethers such as diethyl ether,dioxane or tetrahydrofuran. If the reduction is carried out withdiisobutylaluminum hydride or a sodium alkoxyaluminum hydride, it ispreferable to use hydrocarbons such as hexane or toluene.

Amines or alcohols obtained in this way can be converted in aconventional manner using an alkanoyl halide or anhydride or an aroylhalide or anhydride, expediently in an inert diluent or solvent, e.g. ina lower aliphatic ketone such as acetone, methyl ethyl ketone or methylisobutyl ketone, a dialkylformamide such as dimethylformamide ordiethylformamide or with excess acylating agent as diluent or solvent,into the amides and esters of the formula I according to the invention.The reactions are preferably carried out in the presence of a base asacid-binding agent at from -20° C. to the boiling point of the reactionmixture. Suitable bases are alkali metal carbonates, bicarbonates,hydroxides or alcoholates, especially of sodium and potassium, basicoxides such as aluminum oxide or calcium oxide, organic tertiary basessuch as pyridine or lower trialkylamines such as trimethyl- ortriethylamine. In relation to the acylating agent employed, the basescan be used in a catalytic amount or the stoichiometric amount or in aslight excess.

An alcohol of the formula I (R⁶ ═CH₂ OH) can be etherified with alkylhalides R⁷ --I, R⁷ Br or R⁷ --Cl in the presence of alkali metalhydrides, preferably sodium hydride, or in the presence of alkyllithiumcompounds, preferably n-butyllithium, in an organic solvent such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, methyl tert-butyl etheror, when sodium hydride is used, also in dimethylformamide, at from -10°C. to 40° C.

An alcohol of the formula I can be oxidized to the correspondingaldehyde with suitable oxidizing agents, preferably manganese(IV) oxide,which can be on an inorganic support such as silica gel or alumina. Thisis advantageously carried out in an inert organic solvent, for example ahydrocarbon such as hexane or in an ether such as tetrahydrofuran, or inmixtures of the said solvents and diluents, at from -10° C. to 30° C.The reaction time essentially depends on the oxidizing activity of themanganese(IV) oxide employed.

An aldehyde I (R⁶ ═--CHO) can be obtained by reducing the correspondingnitrile with diisobutylaluminum hydride in a solvent, preferably intoluene, hexane, tetrahydrofuran or mixtures of these solvents, at from-40° C. to room temperature.

Aldehydes and ketones of the formula I are also obtained by hydrolyzingtheir ketals, conventionally in the presence of an acid as catalyst,preferably dilute hydrochloric or sulfuric acid, at from 20° C. up tothe boiling point of the reaction mixture. The reaction is expedientlycarried out in solvents mixed with water, such as acetone, dioxane,tetrahydrofuran, preferably in short-chain alcohols such as methanol andethanol.

A nitrile of the formula I (R⁶ ═--CN) can be hydrolyzed in aconventional manner with acid or, more advantageously, base catalysis tothe corresponding carboxylic acid. Preferred bases are alkali metalhydroxides, especially potassium hydroxide, which is employed in excess.The solvents normally used are water-miscible alcohols such as methanol,ethanol, isopropanol or n-butanol. The reaction is usually carried outat the boiling point of the reaction mixture.

The nitriles I (R⁶ ═--CN) can be converted by addition of an azide, e.g.an alkali metal azide, preferably sodium azide, in the presence ofaluminum chloride or ammonium chloride, into the correspondingtetrazoles. The preferred solvents are cyclic ethers such as dioxane ortetrahydrofuran as well as, in particular, dimethylformamide or mixturesthereof, the reaction generally taking place at from 60° to 100° C.

The acylated phenols of the general formula I (R⁶ ═OCOCH₃) areconverted, if desired, into the free phenols and their physiologicallytolerated salts by hydrolysis. The hydrolysis is expediently carried outin the presence of a diluent, for example a water-miscible ether, suchas 1,2-dimethoxyethane or tetrahydrofuran, or a lower aliphatic alcoholsuch as methanol, ethanol, propanol, isopropanol or butanol, in thepresence or absence of water or in mixtures of the said solvents.Preferred solvents are aqueous mixtures of ethanol or methanol, in whichcase the reaction is carried out at from 20° C. to the boiling point ofthe reaction mixture. The hydrolysis is preferably carried out in thepresence of hydroxides or carbonates of the alkali metal or alkalineearth metals, especially sodium and potassium.

A phenol of the formula I can be converted into the ester according tothe invention in a conventional manner using an alkanoyl halide oranhydride, an aralkanoyl halide or anhydride or an aroyl halide oranhydride, expediently in an inert diluent or solvent, e.g. a loweraliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutylketone, a dialkylformamide such as dimethylformamide or diethylformamideor with excess acylating agent as diluent or solvent. The reactions arepreferably carried out in the presence of a base as acid-binding agentat from -20° C. to the boiling point of the reaction mixture. Suitablebases are alkali metal carbonates, bicarbonates, hydroxides oralcoholates, especially of sodium and potassium, basic oxides such asaluminum oxide or calcium oxide, organic tertiary bases such as pyridineor lower trialkylamines such as trimethyl- or triethylamine. In relationto the alkylating agent employed, the bases can be used in a catalyticamount or the stoichiometric amount of in a slight excess.

The etherification of the phenols of the formula I to aryl ethers of theformula I is advantageously carried out by first converting the phenolinto its salt, and treating the latter with an appropriate alkyl halideor sulfate, preferably an alkyl chloride, bromide or iodide.Particularly suitable deprotonating agents for the preparation of thephenolates in situ are the carbonates, hydroxides and hydrides of thealkali metals. It is expedient to use aprotic polar solvents such asacetone, dimethylformamide, dimethyl sulfoxide or methyl ethyl ketone,in which case the reaction is carried out from 20° C. to the boilingpoint of the reaction mixture.

The acylated thiophenols of the general formula I (R⁶ ═SCOCH₃) areconverted, if desired, into the free thiophenols and theirphysiologically tolerated salts by hydrolysis. The hydrolysis isexpediently carried out in the presence of a diluent, for example awater-miscible ether, such as 1,2-dimethoxyethane or tetrahydrofuran, ora lower aliphatic alcohol such as methanol, ethanol, propanol,isopropanol or butanol, in the presence or absence of water or inmixtures of the said solvents. Preferred solvents are aqueous mixturesof ethanol or methanol, in which case the reaction is carried out atfrom 20° C. to the boiling point of the reaction mixture. The hydrolysisis preferably carried out in the presence of hydroxides or carbonates ofthe alkali metals or alkaline earth metals, especially of sodium andpotassium.

A thiophenol of the formula I can be converted into the ester accordingto the invention in a conventional manner using an alkanoyl halide oranhydride, an aralkanoyl halide or anhydride or an aroyl halide oranhydride, expediently in an inert diluent or solvent, e.g. a loweraliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutylketone, a dialkylformamide such as dimethylformamide or diethylformamideor with excess acylating agent as diluent or solvent. The reactions arepreferably carried out in the presence of a base as acid-binding agentat from -20° C. to the boiling point of the reaction mixture. Suitablebases are alkali metal carbonates, bicarbonates, hydroxides oralcoholates, especially of sodium and potassium, basic oxides such asaluminum oxide or calcium oxide, organic tertiary bases such as pyridineor lower trialkylamines such as trimethyl- or triethylamine. In relationto the alkylating agent employed, the bases can be used in a catalyticamount or the stoichiometric amount or in a slight excess.

The etherification of the thiophenols of the formula I to arylthioethers of the formula I is advantageously carried out by firstconverting the thiophenol into its salt, and treating the latter with anappropriate alkyl halide or sulfate, preferably an alkyl chloride,bromide or iodide. Particularly suitable deprotonating agents for thepreparation of the thiophenolates in situ are the carbonates, hydroxidesand hydrides of the alkali metals. It is expedient to use aprotic polarsolvents such as acetone, dimethylformamide, dimethyl sulfoxide ormethyl ethyl ketone, in which case the reaction is carried out at from20° C. to the boiling point of the reaction mixture.

The thioethers of the formula I (R⁶ ═SR¹²) according to the inventionare, if desired, converted into the corresponding sulfoxides (R⁶ ═SOR¹²)or sulfones (R⁶ ═SO₂ R¹²). The oxidation to sulfoxides is advantageouslycarried out by reacting the thioethers in alcoholic solution withequimolar amounts or an up to 10% excess of periodic acid or of analkali metal salt thereof, preferably with the sodium salt, at from 0°to 30° C. Examples of suitable solubilizers are water, dimethylsulfoxide or amides such as dimethylformamide, as well as ketones suchas acetone. The oxidation to sulfones is advantageously carried out byallowing 2.0 to 3.0 equivalents of the oxidizing agent to act on theappropriate thioether at from -30° to 120° C., preferably -10° to 60° C.Other suitable oxidizing agents are hydrogen peroxide and, inparticular, peroxycarboxylic acids, of which m-chloroperoxybenzoic acidis preferred. Preferred solvents when hydrogen peroxide is used areacetic acid or acetonitrile, and when peroxycarboxylic acids are usedare aprotic solvents such as methylene chloride or toluene.

The thiophenols of the formula I (R⁶ ═SH) can, if desired, be convertedinto the corresponding sulfonic acids by allowing 2 to 5 times the molaramount of hydrogen peroxide to act on the thiophenol, preferably inacetic acid, at from 10° C. to the boiling point of the reactionsolution.

Acid or alkaline hydrolysis of the N-acylated amines of the formula I(R⁶ ═NHR¹⁰ with R¹⁰ ═C₁₋₄ -alkanoyl) according to the invention yieldsthe corresponding aniline derivatives (R⁶ ═NH₂). The hydrolysis isexpediently carried out in the presence of a solvent or diluent, forexample a dialkyl glycol ether or cyclic ether, such as1,2-dimethoxyethane, tetrahydrofuran or dioxane, a lower aliphaticketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone,or in a lower aliphatic alcohol such as methanol, ethanol, propanol orisopropanol or in mixtures of the said solvents with water.

Preferred solvents are aqueous mixtures of ethanol and methanol, inwhich case the reaction is carried out at the boiling point of thereaction mixture.

The alkaline hydrolysis is preferably carried out in the presence ofalkali, such as alkali metal hydroxides, carbonates or bicarbonates,especially of sodium or potassium, organic tertiary bases such aspyridine or lower trialkylamines, such as trimethyl- or triethylamine,mixed with water. The ratio of the base to the ester is stoichiometric,or the base is employed in slight excess. Sodium or potassium hydroxideis preferably used.

The acid hydrolysis is preferably carried out in the presence of mineralacids such as hydrochloric acid, sulfuric acid or phosphoric acid, or oforganic acids such as benzenesulfonic acid or toluenesulfonic acid. Theratio of acid to ester is stoichiometric, or the acid is employed inslight excess. Hydrochloric acid is preferably used.

Anilines (R⁶ ═NH₂) obtained in this way can be converted in aconventional manner using an alkanoyl halide or anhydride or an aroylhalide or anhydride or an alkyl or benzyl halide, expediently in aninert diluent or solvent, e.g. a lower aliphatic ketone such as acetone,methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide suchas dimethylformamide or diethylformamide or with excess acylating agentas diluent or solvent into the amine derivatives of the formula I (R⁶═NR⁹ R¹⁰) according to the invention. The reactions are preferablycarried out in the presence of a base as acid-binding agent at from -20°C. to the boiling point of the reaction mixture. Suitable bases arealkali metal carbonates, bicarbonates, hydroxides or alcoholates,especially of sodium and potassium, basic oxides such as aluminum oxideor calcium oxide, organic tertiary bases such as pyridine or lowertrialkylamines such as trimethyl- or triethylamine. In relation to theacylating or alkylating agent, the bases can be used in a catalyticamount or the stoichiometric amount or in a slight excess.

The phosphonic diesters of the formula I (R⁶ ═PO(OR¹³)₂) can behydrolyzed in a conventional manner to give, depending on the hydrolysisconditions, phosphonic acids or monoesters. Hydrolysis of the phosphonicdiesters with aqueous hydroxides of the alkali metals and alkaline earthmetals, with sodium and potassium hydroxide being preferred, generallyleads to the corresponding phosphonic monoesters. Complete hydrolysis isachieved by reacting the phosphonic diesters with trialkylhalosilanes,preferably trimethylbromo- and trimethyliodosilane, which areadvantageously prepared in situ from trimethylchlorosilane and an alkalimetal bromide or iodide, and subsequent treatment with water or dilutemineral acids, e.g. hydrochloric acid or sulfuric acid.

It is possible to prepare from acids obtained in this way othercompounds according to the invention by conventional procedures. Thus, aphosphonic acid of the formula I can, for example, be converted withphosphorus pentachloride into the phosphonic dichloride, which isreacted with alcohols to give the corresponding esters.

Phosphonic esters or chlorides can be converted by reaction withorganometallic reagents, e.g. Grignard compounds, into correspondingphosphine oxide derivatives.

The compounds according to the invention and their physiologicallytolerated salts can, by reason of their pharmacological properties, beused for the topical and systemic therapy and prophylaxis ofprecanceroses and carcinomas of the skin, the mucous membranes andinternal organs and for the topical and systemic therapy of acne,psoriasis and other dermatological disorders associated withpathological keratinization, especially ichthyosis, darier's disease,herpes, leukoplakia and eczema, but also vitiligo, warts, phototoxis(premature ageing) of the skin, and dry eyes and other corneopathies andfor the treatment of rheumatic disorders, especially those of aninflammatory or degenerative nature and which affect joints, muscles,tendons and other parts of the locomotor system. Preferred indicationsare: the therapy of dermatological disorders, of skin damage caused bysunlight, and of iatrogenic skin damage, e.g. atrophy induced bycorticosteroids, and the prophylactic treatment of precanceroses andtumors.

The pharmacological effects can be shown, for example, in the followingtests: the compounds according to the invention abolish thekeratinization which starts in hamster tracheal tissue in vitro aftervitamin A deficiency. The keratinization is part of the early phase ofcarcinogenesis, which is inhibited by the compounds of the formula Iaccording to the invention in a similar test in vivo after initiation bychemical compounds, by energetic radiation or after viral celltransformation. These methods are described in Cancer Res. 36 (1972)964-972 and Nature 250 (1974) 64-66 and 253, (1975) 47-50.

In addition, the compounds according to the invention inhibit theproliferation of certain malignant cells. This method is described in J.Natl. Cancer Inst. 60 (1978) 1035-1041, Experimental Cell Research 117(1978) 15-22 and Proc. Natl. Acad. Sci. USA 77 (1980) 2937-2940.

The antiarthritic effect of the compounds according to the invention canbe determined in a conventional manner in animal experiments using theadjuvant arthritis or Streptococci cell wall induced arthritis model.The dermatological activity, for example for the treatment of acne, canbe demonstrated, inter alia, by the comedolytic activity and the abilityto reduce the number of cysts in the rhino mouse model.

The latter method is described by L. H. Kligman et al. in the Journal ofInvestigative Dermatology 73 (1978) 354-358.

The dermatological activity can also be measured by the reduction insebaceous glands and the associated diminution in sebum production bythe flank organ of the hamster. This method is described by E. C. Gomezin J. Am. Dermatol. 6 (1982) 746-750.

Furthermore, it is possible to determine the reversal which can beachieved with compounds according to the invention of skin damage causedby UV light in animal models. This method is described by L. H. Kligmanet al. in Connect. Tissue Res. 12 (1984) 139-150 and in the Journal ofthe American Academy of Dermatology 15 (1986) 779-785.

Accordingly, the invention furthermore relates to therapeutic agents fortopical and systemic administration and to cosmetic agents which containa compound of the formula I as active substance in addition toconventional carriers or diluents.

The agents can accordingly be administered orally, parenterally ortopically. Examples of suitable formulations are uncoated or(film-)coated tablets, capsules, pills, powders, solutions orsuspensions, infusion or injection solutions and pastes, ointments,gels, creams, lotions, dusting powders, solutions or emulsions andsprays.

The therapeutic or cosmetic agents can contain the compounds to be usedaccording to the invention in a concentration of 0.001 to 1%, preferably0.001 to 0.1%, for local use, and preferably in a single dose of 0.1 to250 mg for systemic use as a therapeutic agent, and are administered inone or more doses each day depending on the nature and severity of thedisorders.

Appropriate tablets can be obtained, for example, by mixing the activesubstance with known auxiliaries, for example inert diluents such asdextrose, sugar, sorbitol, mannitol or polyvinylpyrrolidone,disintegrants, such as corn starch or alginic acid, binders such asstarch or gelatin, lubricants such as magnesium stearate or talc and/oragents to achieve a depot effect, such as carboxypolymethylene,carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate. The tablets can also be composed of several layers.

Appropriate coated tablets can be produced by coating cores, which havebeen produced in a similar manner to the tablets, with conventionalcoating agents, for example polyvinylpyrrolidone or shellac, gum arabic,talc, titanium dioxide or sugar. The coating can also be composed ofseveral layers, it being possible to use the auxiliaries mentioned abovefor tablets.

Solutions or suspensions containing the active substance according tothe invention can additionally contain taste corrigents such assaccharin, cyclamate or sugar as well as, for example, flavorings suchas vanillin or orange extract. They can moreover contain suspendingauxiliaries such as sodium carboxymethylcellulose or preservatives suchas p-hydroxybenzoates. Capsules containing active substances can beproduced, for example, by the active substance being mixed with an inertcarrier such as lactose or sorbitol and encapsulated in gelatincapsules.

Examples of conventional ingredients of cosmetic and pharmaceuticalformulations for topical use are: anionic, cationic and nonionicemulsifiers and emulsion stabilizers which can simultaneously act asbodying agents or gel formers, such as polyvinylpyrrolidone, fattyalcohols, glycerol monostearate, polyacrylic acids, cellulosederivatives and ethylene oxide/propylene oxide block polymers, solid orliquid oily components or fats of mineral, vegetable or animal origin,synthetic oily esters such as triglyceride esters and isopropylmyristate, hydrophilic components such as glycerol, polyethylene glycoland propylene glycol.

Examples of further ingredients of cosmetics are sunscreen agents,suntan agents, preservatives, anti-oxidants, pigments, colorants,essential oils and perfume oils, vitamins, plant extracts, collagen etc.These substances are described, for example, in the CTFA CosmeticIngredient Dictionary, 3rd edition, Washington 1982.

The examples which follow illustrate the invention:

Preparation of Starting Compounds EXAMPLE A5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthol

27.5 g (0.2 mol) of anhydrous aluminum chloride were added by spatula to250.0 g (2.65 mol) of phenol plus 414.5 g (2.27 mol) of2,5-dichloro-2,5-dimethylhexane in 500 ml of petroleum ether at roomtemperature while stirring. After 48 hours, the reaction mixture waspoured into ice-water and extracted with ether, and the organic phasewas washed to neutrality with water, dried over sodium sulfate andevaporated under reduced pressure. Two recrystallizations of the residuefrom methanol yielded 148.7 g of the title compound of melting point219°-220° C.

EXAMPLE B 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength)were mixed while cooling and then added dropwise within 2 hours to asolution of 65.8 g (0.35 mol) of1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacialacetic acid and 257 ml of acetic anhydride in a salt/ice bath. After theaddition was complete, the reaction mixture was warmed to roomtemperature and stirred overnight. The solution was then poured intowater, and the precipitate was filtered off with suction, washed withwater and dried. 79.7 g of crude2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of meltingpoint 46°-50° C. were obtained.

25 g of this crude product were hydrogenated in a mixture of 65 ml ofdioxane, 65 ml of methanol and 5 ml of water on 0.3 g of palladium onactive carbon (10%) at 100° C. and under 200 bar of hydrogen in anautoclave for 48 hours. After the reaction was complete, the catalystwas filtered off, and the solution was evaporated. Recrystallization ofthe residue from n-heptane yielded 17.6 g of the title compound ofmelting point 63°-65° C.

EXAMPLE C 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-thionaphthol

94.0 g (0.5 mol) of 1,2,3,4-tetrahydro-1,1,4,4tetramethylnaphthalenewere stirred into 100 ml of chlorosulfonic acid at 20° C. within 30 min.The reaction solution was maintained at 60° C. for 1 hour, cooled toroom temperature and then poured into 1.5 1 of ice and extracted withether. The organic phase was washed to neutrality with brine and water,dried over magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from methanol yielded 55.0 g of5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-sulfonyl chloride ofmelting point 71°-74° C.

57.5 g (0.2 mol) of this sulfonyl chloride in 150 ml of drytetrahydrofuran were added dropwise at room temperature within 2 hoursto a suspension of 15.4 g (0.4 mol) of lithium aluminum hydride in 150ml of dry tetrahydrofuran. The reaction solution was stirred at roomtemperature for 1 hour, and then 25 ml of water followed by 50 ml ofsaturated tartaric acid solution were added dropwise, and the mixturewas boiled for a few minutes. The solution was cooled, anhydrousmagnesium sulfate was added until clear, and the precipitate wasfiltered off with suction.

Evaporation of the filtrate yielded 33.0 g of the title compound as aresin (R_(f) =0.4, 7:3 heptane/ethyl acetate).

Preparation of the Final Products EXAMPLE 1 4-Cyanobenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

40.8 g (0.2 mol) of 5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthol,30.4 g (0.2 mol) of 4-cyanobenzyl chloride and 80 g (1.2 mol) ofanhydrous potassium carbonate in 400 ml of butanone and 300 ml ofdimethylformamide were refluxed for 9 h. The mixture was cooled and thenpoured into 1.5 1 of water, and the solid was filtered off with suctionand washed with water. Drying resulted in 63 g of the title compound ofmelting point 149°-150° C.

EXAMPLE 2 4-Carboxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

20 g (0.063 mol) of 4-cyanobenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether were refluxedwith 163 ml of 10N sodium hydroxide solution in 245 ml of ethanol for 2h. The mixture was cooled and then poured into water, which was thenacidified with hydrochloric acid, and the precipitate was filtered offwith suction and washed with water and methanol. Drying resulted in 19.7g of the title compound of melting point >330° C.

EXAMPLE 3 4-Formylbenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

15.5 ml (19.7 mmol) of diisobutylaluminum hydride solution (20% inhexane) were added dropwise under nitrogen to a solution of 3 g (9.4mmol) of 4-cyanobenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylether in 40 ml of dry ether at 25° C. The mixture was stirred at 25° C.for 40 min and then 250 ml of saturated tartaric acid solution wereadded dropwise. Subsequently, a little sodium sulfate solution wasadded, and the phases were separated. The aqueous phase was extractedwith ether, and the organic extract was washed with saturated tartaricacid solution and water, dried over Na₂ SO₄ and concentrated.Recrystallization from methanol resulted in 1.4 g of the title compoundof melting point 102°-104° C.

EXAMPLE 4 4-Carbamoylmethylbenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

2 g (6.3 mmol) of 4-cyanobenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether and 5.9 g ofpotassium hydroxide powder in 47.5 ml of tert-butanol were refluxed for45 min. The reaction mixture was cooled and then poured into saturatedbrine and extracted with ether. The precipitate from the ether phase wasfiltered off with suction and recrystallized from isopropanol. Thisresulted in 1.3 g of the title compound of melting point 202°-205° C. Afurther 0.5 g of the product was obtained from the ether phase byconventional working up.

EXAMPLE 5 4-Aminomethylbenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

A suspension of 3 g (9.4 mmol) of 4-cyanobenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether in 60 ml ofether was added dropwise under nitrogen to a suspension of 1 g (26 mmol)of lithium aluminum hydride in 50 ml of dry ether at 25° C. The mixturewas then stirred under reflux for 3 h, cooled and hydrolyzed cautiouslywith water and sodium sulfate solution. The mixture was extracted threetimes with ether, and the combined ether extracts were washed withwater, dried over Na₂ SO₄ and concentrated. 3 g of the title compound ofmelting point 77°-79° C. remained.

EXAMPLE 6 4-Hydroxymethylbenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

A solution of 0.97 g (9 mmol) of ethyl chloroformate in 5 ml oftetrahydrofuran was added dropwise to a solution of 3 g (9 mmol) of4-carboxybenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl etherand 0.9 g (9 mmol) of triethylamine in 20 ml of dry tetrahydrofuran at0° C. The mixture was stirred at 0° C. for 30 min, the solid wasfiltered off, and the filtrate was added dropwise to a solution of 0.83g (22 mmol) of sodium borohydride in 8 ml of tetrahydrofuran and 8 ml ofwater. The reaction mixture was then allowed to reach room temperaturewithin 1 h and was then acidified with 1N hydrochloric acid. Most of thetetrahydrofuran was removed in a rotary evaporator, and the remainingaqueous phase was extracted with chloroform. The organic phase was driedover Na₂ SO₄ and concentrated. Fractional crystallization from ethylacetate, discarding the first fraction, resulted in 1.1 g of the titlecompound of melting point 108°-109° C.

EXAMPLE 7 4-Carbethoxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether

2 g (6 mmol) of 4-carboxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether, 2.7 g (19.6mmol) of anhydrous potassium carbonate and 19 g (12.4 mmol) ofiodoethane in 18 ml of butanone were refluxed for 7 h. The mixture wasthen poured into water and extracted with ether, and the organic phasewas washed with water, dried over Na₂ SO₄ and concentrated.Recrystallization from methanol resulted in 0.9 g of the title compoundof melting point 76°-77° C.

EXAMPLE 8 4-Carbethoxyphenyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl ether

10 g (36 mmol) of2-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6 g (36mmol) of ethyl 4-hydroxybenzoate and 7.2 g (52 mmol) of anhydrouspotassium carbonate in 60 ml of dimethylformamide were refluxed for 5.25h. The mixture was then poured into water and extracted several timeswith ether, and the organic phase was washed with water, dried over Na₂SO₄ and concentrated. Recrystallization from methanol resulted in 6.7 gof the title compound of melting point 109°-11° C.

EXAMPLE 9 4-Carboxyphenyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl ether

In a similar manner to Example 2, 2.6 g of the title compound of meltingpoint 185°-186° C. are obtained from 3 g (8.5 mmol) of4-carbethoxyphenyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl ether.

EXAMPLE 10 4-Carboxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl thioether

5.7 g (26 mmol) of 4-bromomethylbenzoic acid in 20 ml ofdimethylformamide were added to 6.6 g (30 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-thionaphthol and 3.5 g (30mmol) of potassium tert-butanolate in 80 ml of dimethylformamide at roomtemperature. After the reaction solution had been stirred at roomtemperature overnight it was poured into water and extracted with ethylacetate. The organic extract was washed with water, dried over magnesiumsulfate and evaporated under reduced pressure. Recrystallization of theresidue from cyclohexane yielded 4.0 g of the title compound of meltingpoint 169°-170° C.

EXAMPLE 11N-(4-carboxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

8.1 g (40 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine and 6.6 g (40mmol) of methyl 4-formylbenzoate in 100 ml of toluene were refluxed for30 min, the solvent was evaporated off, the residue was taken up in 200ml of 1:1 tetrahydrofuran/methanol, and 3.2 g (50 mmol) of sodiumcyanoborohydride were added at room temperature. After the mixture hadbeen stirred for 2 hours, the solvent was evaporated off under reducedpressure, the residue was taken up in 200 ml of ethyl acetate, and theorganic phase was washed with water, dried over magnesium sulfate andevaporated.

Recrystallization of the residue from ethanol yielded 9.6 g ofN-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamineof melting point 104°∝107° C.

2 g of this ester and 2.5 g of potassium hydroxide in 45 ml of 5:1:3ethanol/dimethyl sulfoxide/water were refluxed for 1 hour. At roomtemperature, 20 ml of 2N hydrochloric acid were added to the solution.The precipitate was filtered off, recrystallized from methanol andyielded 1.1 g of the title compound of melting point 225°-231° C.

EXAMPLE 12N-Acetyl-N-(4-carboxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

4.2 g (12 mmol) ofN-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine(from Example 11) and 1.6 ml (16 mmol) of acetic anhydride and 2.3 ml(17 mmol) of triethylamine in 100 ml of dichloromethane were stirred atroom temperature. After the reaction was complete, the solution waspoured into water and extracted with ethyl acetate, and the organicphase was separated off and evaporated; the residue was recrystallizedfrom ethanol and yieldedN-acetyl-N-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine.2.5 g of this product and 5.0 g of potassium hydroxide in 90 ml of 5:3:1ethanol/water/dimethyl sulfoxide were then refluxed for 1 hour and,after cooling, three times the volume of ice-water was added and the pHwas adjusted to 4 with 2N hydrochloric acid. The precipitate wasfiltered off and dried, yielding 1.5 g of the title compound of meltingpoint 219°-223° C.

EXAMPLE 13N-Methyl-N-(4-carboxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

4.2 g (12 mmol) ofN-(4-carbomethoxybenzyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine(from Example 11), 2.0 g (30 mmol) of paraformaldehyde and 1.25 g (20mmol) of sodium cyanoborohydride in 100 ml of 1:1methanol/tetrahydrofuran were stirred at room temperature overnight andthen at 40° C. for 2 hours. The solvent was evaporated off, the residuewas taken up in ethyl acetate, and the solution was washed with water,dried over magnesium sulfate and evaporated.

The residue was refluxed with 5 g of potassium hydroxide in 90 ml of5:3:1 ethanol/water/dimethyl sulfoxide for 1 hour. At room temperature,the reaction solution was adjusted to pH 5 with 2N hydrochloric acid.The resulting precipitate was filtered off and recrystallized fromethanol, yielding 2.5 g of the title compound of melting point 141°-144°C.

EXAMPLE 14 4-Carboxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl sulfoxide

A solution of 3.4 g (16 mmol) of sodium periodate in 30 ml of water wasadded dropwise to 5.3 g (15 mmol) of the thioether from Example 10 in amixture of 150 ml of ethanol and 40 ml of dimethylformamide at 0° C.,and the mixture was then stirred at the same temperature for 2 hours andat room temperature overnight. The reaction solution was then pouredinto water, the pH was adjusted to 5 with 2N hydrochloric acid, themixture was extracted with dichloromethane, and the organic extractswere washed with water, dried over magnesium sulfate and evaporatedunder reduced pressure. Crystallization of the oily residue from ethanolyielded 2.2 g of title compound of melting point 198°-200° C.

EXAMPLE 15 4-Carboxybenzyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl sulfone

6.2 g (54 mmol) of hydrogen peroxide solution (30% strength in water)were added dropwise to 6.3 g (18 mmol) of the thioether from Example 10in 60 ml of glacial acetic acid at 50° C. The solution was stirred at75° C. for 1 hour, the reaction product was precipitated with water, andthe precipitate was filtered off with suction.

Recrystallization from ethanol yielded 1.6 g of the title compound ofmelting point 202°-205° C.

The substances in the following table were prepared in a similar manner.

    TABLE 1      Ex. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 A m.p. (°     C.)       16 H H HC(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2     CO.sub.2 H CH.sub.2 N(COCH.sub.3) 228-230 17 H H H C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H CH.sub.2 NH 193-195 18 H     H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     CH.sub.2 S 197-199 19 H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2      C(CH.sub.3).sub.2  CO.sub.2      H CH(CH.sub.3)S 172-175 20 H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     C(CH.sub.3).sub.2  CO.sub.2      H SCH(CH.sub.3) 138-140 21 H H H C(CH.sub.3).sub.2 CH.sub. 2 CH.sub.2     C(CH.sub.3).sub.2  CO.sub.2 H CH.sub.2 N(CH.sub.3) 253-258 22 OCH.sub.3     H OCH.sub.3 C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2     CO.sub.2 H NHCH.sub.2 172-175 23 OCH.sub.3 H OCH.sub.3 C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H N(COCH.sub.3)CH.sub.2     190-193 24 OH H OH C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2      CO.sub.2 H OCH.sub.2  190-196 25 CH.sub.3 CH.sub.3 H C(CH.sub.3).sub.3     H CO.sub.2 H NHCH.sub.2  140-142 26 H H H C(CH.sub.3).sub.3 H CO.sub.2 H N     HCH.sub.2  266-268 27 H CH.sub.3 H H C(CH.sub.3).sub.3 CO.sub.2 H     NHCH.sub.2  158-162 28 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     CO.sub.2      H NHCH.sub. 2 195-198 29 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     CO.sub.2 H OCH.sub.2  198-207 30 H H H C(CH.sub.3).sub.3 H CO.sub.2 H     OCH.sub.2  233-242 31 H H H C(CH.sub.3).sub.2 C.sub.2 H.sub.5 H CO.sub.2     H OCH.sub.2  208-213 32 C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 H H     CO.sub.2 H OCH.sub.2  230-235 33 H CH.sub.3 H C(CH.sub.3).sub.3 H     CO.sub.2 H OCH.sub.2       193-198 34 C(CH.sub.3).sub.3 H CH.sub.3 C(CH.sub.3).sub.3 H CO.sub.2 H O     CH.sub.2  235-238 35 C(CH.sub.3).sub.3 H H CH.sub.3 H CO.sub.2 H     OCH.sub.2  210-212 36 H H C(CH.sub.3).sub.3 H H CO.sub.2 H OCH.sub.2     181-184 37 H CH(CH.sub.3)C.sub.2 H.sub.5 H C(CH.sub.3).sub.3 H CO.sub.2     H OCH.sub.2       208-215 38 C(CH.sub.3).sub.3 CH(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 H     CO.sub.2 H OCH.sub.2       202-210 39 H OH C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CO.sub.2 H     OCH.sub.2  210-212 40 C(CH.sub.3).sub.3 H H C(CH.sub.3).sub.3 H CO.sub.2     H OCH.sub.2  248-250 41 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 H H H     CO.sub.2 H OCH.sub.2  42 OCOCH.sub.3 H OCOCH.sub.3 C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H OCH.sub.2  164-168 43 H     H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     NHCH(CH.sub.3) 205-208 44 H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     C(CH.sub.3).sub.2  H OCH.sub.2       45 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OC(CH.sub. 3).sub.3     OCH.sub.2  46 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3OCH.sub.3     OCH.sub.2  47 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OH OCH.sub.2  48     H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OCOCH.sub.3 OCH.sub.2  49 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OCH.sub.2 CO.sub.2 H OCH.sub.2  50     H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OCH.sub.2 CO.sub.2 C.sub.2     H.sub.5 OCH.sub.2       51 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 NHCOCH.sub.3 OCH.sub.2     52 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 NH.sub.2 OCH.sub.2  53 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CN OCH.sub.2  113-115 54 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CHO OCH.sub.2   97-100 55 H H     C(CH.sub.3).sub.3 H C(CH.sub. 3).sub.3 CH.sub.2 OH OCH.sub.2  93-97 56 H     H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CH.sub.2 NH.sub.2 OCH.sub.2     129-132 57 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 SO.sub.3      H OCH.sub.2  58 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 SH OCH.sub.2     59 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 SO.sub.2 C.sub.2 H.sub.5     OCH.sub.2       126-130 60 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 PO(OH).sub.2     OCH.sub.2  61 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 PO(OC.sub.2     H.sub.5).sub.2 OCH.sub.2  62 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     N(CH.sub.3).sub.2 OCH.sub.2       63 CH.sub.3 CH.sub.3 CH.sub.3 OC(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     CO.sub.2 H OCH.sub.2       193-196 64 CH.sub. 3 CH.sub.3 CH.sub.3 OC(CH.sub.3)(C.sub.2 H.sub.4     OH)CH.sub.2 CH.sub.2  CO.sub.2 H OCH.sub.2  179-183 65 CH.sub.3 CH.sub.3     CH.sub.3 OC(CH.sub.3)(C.sub.2 H.sub.4 OCOCH.sub.3)CH.sub.2 CH.sub.2     CO.sub.2 H OCH.sub.2  66 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     OC(CH.sub.3).sub.3 NHCH.sub.2        67 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OH NHCH.sub.2  68 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OC(CH.sub.3).sub.3 NHCH.sub.2  69     H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CH.sub.2 OH NHCH.sub.2  70 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 SO.sub.3 H NHCH.sub.2  71 H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CONH.sub.2 NOCH.sub.2  183-187 72     H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 NHCOCH.sub.3  NHCH.sub.2  73 H     H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CO.sub.2 H SCH.sub.2  149-152 74     H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OC(CH.sub.3).sub.3 SCH.sub.2     75 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 OH SCH.sub.2  76 CH.sub.3 H     H C(CH.sub.3).sub.3 H CO.sub.2 H SCH.sub.2  77 H H H C(CH.sub.3).sub.3     HCO.sub.2 H SCH.sub.2  78 H H H C(CH.sub.3).sub.2 CH.sub.2      COC(CH.sub.3).sub.2  CO.sub.2 H CH.sub.2 NH  79 H H H C(CH.sub.3).sub.2     CH.sub.2 CH(OH)C(CH.sub.3).sub.2 CO.sub.2 H CH.sub.2 NH 234-236 80 H H H C     (CH.sub.3).sub.2 CHCHC(CH.sub.3).sub.2 CO.sub.2 H CH.sub.2 NH 81 H H     C(CH.sub.3).sub.3 OH C(CH.sub.3).sub.3  CO.sub.2 H CH.sub.2 NH  82 H H     C(CH.sub.3).sub.3 OH C(CH.sub.3).sub.3 SH CH.sub.2      NH 83 H H C(CH.sub.3).sub.3 OH C(CH.sub.3).sub.3 SCOCH.sub.3 CH.sub.2     NH 84 H H C(CH.sub.3).sub.3 OH C(CH.sub.3).sub.3 SCH.sub.3 CH.sub.2 NH     85 H HC(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 SO.sub.2 CH.sub.3 CH.sub.2 O     86 H HC(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 N(CH.sub.3).sub.2 CH.sub.2 O     87 H H H C(CH.sub.3).sub.3 H CO.sub.2 H CH.sub.2 NH 106-110 88 H H H     C(CH.sub.3).sub.2 OCH.sub.3 H CO.sub.2 H CH.sub.2      NH 89 H H H C(CH.sub.3).sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2  CO.sub.2 H C     H.sub.2 NH  90 OCH.sub.3 OCH.sub.3 H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     C(CH.sub.3).sub.2   CO.sub.2 H CH.sub.2 NH 91 OC.sub.4 H.sub.9 CH.sub.3     H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     CH.sub.2 NH 92 OCH.sub.3 OCH.sub.3 H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     C(CH.sub.3).sub.2  CO.sub.2 C.sub.2 H.sub.5  CH.sub.2 NH 130-132 93 H H     H C(CH.sub.3).sub.2 OCH.sub.3 H CO.sub.2 C.sub.2 H.sub.5 CH.sub.2 NH     75-77 94 H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 NO.sub.2 OCH.sub.2     127-129 95 CH.sub.3 CH.sub.3 CH.sub.3 OC(CH.sub.3).sub.2 CH.sub.2     CH.sub.2  CO.sub.2 C.sub.2 H.sub.5  OCH.sub.2  76-77 96 H OCH.sub.3 H     C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     CH.sub.2 NH  97 H F H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2      C(CH.sub.3).sub.2  CO.sub.2 H CH.sub.2 NH 98 Cl Cl H C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H CH.sub.2 O 99 Cl H Cl     C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     NHCH.sub.2  100  H H H OC(CH.sub.3).sub.3 OCH.sub.3 CO.sub.2 H CH.sub.2     NH 101  H H H C(CH.sub.3).sub.2 CH(OH)CH.sub.2 C(CH.sub.3).sub.2     CO.sub.2 H CH(CH.sub.3)NH 102  H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 P     O(OC.sub.2 H.sub.5).sub.2 OCH.sub.2  103  H H C(CH.sub.3).sub.3 H     C(CH.sub.3).sub.3 PO(OH).sub.2 OCH.sub.2  104  H H C(CH.sub.3).sub.3 H     C(CH.sub.3).sub.3 PO(OCH).sub.2 OCH.sub.2  105  H H H C(CH.sub.3).sub.2     CH(CH.sub.3)C(CH.sub.3).sub.2  CO.sub.2 H NHCH.sub.2  106       H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CCH(OCH.sub.3).sub.2     NHCH.sub.2  107       H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CHO NHCH.sub.2   108  H H     C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3      ##STR14##      OCH.sub.2   109       H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     ##STR15##      OCH.sub.2   110  H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 CO.sub.2     CH.sub.2 C.sub.6 H.sub.5 OCH.sub.2   111  H H C(CH.sub.3).sub.3 H     C(CH.sub.3).sub.3      ##STR16##      OCH.sub.2   112  H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3 NHCOC.sub.6     H.sub.5 OCH.sub.2  113  H H C(CH.sub.3).sub.3 H C(CH.sub.3).sub.3     N(COCH.sub.3)CH.sub.2 C.sub.6 H.sub.5 OCH.sub.2  114       H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2       PO(OH).sub.2 OCH.sub.2  115  H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C     (CH.sub.3).sub.2  CO.sub.2 H SCH(CH.sub.3) 181-185 116       H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2      NHCOCH.sub.3 NHCH.sub.2  192-195 117  H H H C(CH.sub.3).sub.2 CH.sub.2     CH.sub.2 C(CH.sub.3).sub.2  SCH.sub.3 NHCH.sub.2  83-85 118  H NO.sub.2     H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  CO.sub.2 H     OCH.sub.2  235-237 119  H NO.sub.2 H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C     (CH.sub.3).sub.2  CO.sub.2 CH.sub.3 OCH.sub.2  190-192 120       H H OCH.sub.3 OH OCH.sub.3 CO.sub.2 C.sub.2 H.sub.5 CH.sub.2 NH     123-125 121  H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 S     O.sub.2 CH.sub.3 CH.sub.2 O 158-160 122  H H H C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  N(CH.sub.3).sub.2 NHCH.sub.2     113-115 123  H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2      SCH.sub.3  CH.sub.2 O 91-94 124  H H H C(CH.sub.3).sub.2 CH.sub.2     CH.sub.2 C(CH.sub.3).sub.2  NHCOCH.sub.3 CH.sub.2 S 115-117 125  H H H     C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2  NHCOCH.sub.3     CH.sub.2 O 126-128 126  H H H C(CH.sub.3).sub.3 H OH SCH.sub.2  85-87     127  H H H C(CH.sub.3).sub.3 H OC(CH.sub.3).sub.3 SCH.sub.2  83-85 128     CH.sub.3 CH.sub.3 CH.sub.3 OC(CH.sub.3).sub.2 CH.sub.2 CH.sub.2     SO.sub.2 C.sub.2 H.sub.5 OCH.sub.2  94-97 129  H H C(CH.sub.3).sub.3 H     C(CH.sub.3).sub.3 CONHOH OCH.sub.2  158-160 130  H H H C(CH.sub.3).sub.2     CH.sub.2 CH.sub.2 C(CH.sub.3).sub. 2  SOC.sub.2 H.sub.5 NHCH.sub.2     154-155 131  H H H C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2      SO.sub.2 C.sub.2 H.sub.5 NHCH.sub.2  140-143 132  H H C(CH.sub.3).sub.3 H      C(CH.sub.3).sub.3 CONHOCH.sub.3 OCH.sub.2  133  H H C(CH.sub.3).sub.3 H     C(CH.sub.3).sub.2 CON(CH.sub.3)OCH.sub.3 OCH.sub.2

Examples of Pharmaceutical Formulations: EXAMPLE I

    ______________________________________                                        Tablet containing 250 mg of active substance                                  Composition for 1000 tablets:                                                 ______________________________________                                        Active substance of Example No. 2:                                                                   250 g                                                  Potato starch:         100 g                                                  Lactose:                50 g                                                  4% gelatin solution:    45 g                                                  Talc:                   10 g                                                  ______________________________________                                    

Preparation

The finely powdered active substance, potato starch and lactose aremixed. The mixture is moistened with about 45 g of 4% gelatin solution,converted into fine granules and dried. The dry granules are screened,mixed with 10 g of talc and compressed to tablets in a rotary tabletingmachine. The tablets are packed into tightly sealed polypropylenecontainers.

EXAMPLE II

    ______________________________________                                        Cream containing 0.1% active substance                                        ______________________________________                                        Active substance of Example No. 10:                                                                   0.1       g                                           Glycerol monostearate:  10.0      g                                           Cetyl alcohol:          4.0       g                                           Polyethylene glycol 400 stearate:                                                                     10.0      g                                           Polyethylene glycol sorbitan monostearate:                                                            10.0      g                                           Propylene glycol:       6.0       g                                           Methyl p-hydroxybenzoate:                                                                             0.2       g                                           Demineralized water:    ad 100.0  g                                           ______________________________________                                    

Preparation

The very finely powdered active substance is suspended in 1,2-propyleneglycol and the suspension is stirred into the molten mixture of glycerolmonostearate, cetyl alcohol, polyethylene glycol 400 stearate andpolyethylene glycol sorbitan monostearate at 65° C. A solution of methylp-hydroxybenzoate in water at 70° C. is emulsified in this mixture.After the cream has cooled it is homogenized in a colloid mill andpacked into tubes.

EXAMPLE III

    ______________________________________                                        Dusting powder containing 0.1% active substance                               ______________________________________                                        Active substance of Example No. 11:                                                                    0.1    g                                             Zinc oxide:              10.0   g                                             Magnesium oxide:         10.0   g                                             Highly disperse silica:  2.5    g                                             Magnesium stearate:      1.0    g                                             Talc:                    76.4   g                                             ______________________________________                                    

Preparation

The active substance is micronized and mixed homogeneously with theother ingredients in an air-jet mill. The mixture is forced through ascreen (mesh No. 7) and packed into polyethylene containers with asprinkle top.

We claim:
 1. A diphenylheteroaklyl derivative of the formula I or Ia##STR17## wherein A is --X--CH₂ --, --X--CH(CH₃)--, --CH₂ --X-- or--(CH₃)CH--X--, X is oxygen, or --S(O)_(n) -- with n being 0, 1, or 2and R is --S(O)_(n) C₁₋₄ alkyl, with n being 0, 1 or 2,;or thephysiologically tolerated salts thereof.
 2. A diphenylheteroalkylderivative as claimed in claim 1 wherein A is --CH₂ --X--, X is oxygenand R is --SO₂ CH₃.